Mar 23, 2016 - if the company provides ruxolitinib with the discount agreed in the ... starting dose is 15 mg twice dail
Rux Ruxolitinib olitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis Technology appraisal guidance Published: 23 March 2016 nice.org.uk/guidance/ta386
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Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis (TA386)
Your responsibility The recommendations in this guidance represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, health professionals are expected to take this guidance fully into account, alongside the individual needs, preferences and values of their patients. The application of the recommendations in this guidance are at the discretion of health professionals and their individual patients and do not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian. Commissioners and/or providers have a responsibility to provide the funding required to enable the guidance to be applied when individual health professionals and their patients wish to use it, in accordance with the NHS Constitution. They should do so in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible.
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Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis (TA386)
Contents 1 Recommendations ......................................................................................................................................................... 4 2 The technology ................................................................................................................................................................ 5 3 Evidence ............................................................................................................................................................................. 6 Clinical effectiveness.....................................................................................................................................................................
6
Cost effectiveness .......................................................................................................................................................................... 13 Evidence review group comments ........................................................................................................................................... 19
4 Committee discussion .................................................................................................................................................. 24 Clinical effectiveness..................................................................................................................................................................... 25 Cost effectiveness .......................................................................................................................................................................... 28 Summary of appraisal committee's key conclusions ......................................................................................................... 32
5 Implementation............................................................................................................................................................... 41 6 Review of guidance ........................................................................................................................................................ 42 7 Appraisal committee members, guideline representatives and NICE project team ........................... 43 Appraisal committee members.................................................................................................................................................. 43 NICE project team .......................................................................................................................................................................... 45
8 Sources of evidence considered by the committee .......................................................................................... 46
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Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis (TA386)
This guidance replaces TA289.
1
Recommendations
1.1
Ruxolitinib is recommended as an option for treating disease-related splenomegaly or symptoms in adults with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis, only: in people with intermediate-2 or high-risk disease, and if the company provides ruxolitinib with the discount agreed in the patient access scheme.
1.2
People whose treatment with ruxolitinib is not recommended in this NICE guidance, but was started within the NHS before this guidance was published, should be able to continue treatment until they and their NHS clinician consider it appropriate to stop.
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Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis (TA386)
2
The technology
2.1
Ruxolitinib (Jakavi, Novartis) is a protein kinase inhibitor that targets Janusassociated kinase (JAK) signalling. Ruxolitinib has a UK marketing authorisation for 'the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis'. It is administered orally. The recommended starting dose is 15 mg twice daily for patients with a platelet count between 100,000/mm3 and 200,000/mm3, and 20 mg twice daily for patients with a platelet count of more than 200,000/mm3. The maximum recommended starting dose for patients with platelet counts between 50,000/mm3 and 100,000/mm3 is 5 mg twice daily.
2.2
The summary of product characteristics lists the following adverse reactions for ruxolitinib: anaemia, thrombocytopenia, neutropenia, bleeding and weight gain. For full details of adverse reactions and contraindications, see the summary of product characteristics.
2.3
The cost of ruxolitinib is £3,360 for a 56-tablet pack of 10 mg, 15 mg or 20 mg tablets, or £1,680 for a 56-tablet pack of 5 mg tablets (British national formulary [BNF], December 2015). This amounts to an annual cost of about £43,680 per patient (assuming a 15 mg or 20 mg dose, taken twice daily, for 52 weeks). The company has agreed a patient access scheme with the Department of Health. This scheme provides a simple discount to the list price of ruxolitinib with the discount applied at the point of purchase or invoice. The level of the discount is commercial in confidence. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS.
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Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis (TA386)
3
Evidence
The appraisal committee (section 7) considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG; section 8). See the committee papers for full details of the evidence.
Clinical effectiveness 3.1
The company conducted a systematic literature review for clinical trials investigating ruxolitinib that included patients with primary myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis. Two randomised controlled trials were identified that met the inclusion criteria: COMFORT-I and COMFORT-II. The company also included supportive evidence from 4 non-randomised controlled studies of ruxolitinib in patients with intermediate-1 risk myelofibrosis or a low platelet count (ROBUST, JUMP, Study 258 and EXPAND).
Ov Overview erview of the rrandomised andomised controlled trials 3.2
COMFORT-I is a multicentre (USA, Canada and Australia), phase III, randomised, double-blinded trial that compared ruxolitinib (15 mg or 20 mg twice daily, n=155) with placebo (n=154) in people with primary myelofibrosis (45.2% of ruxolitinib group; 54.5% of placebo group), or myelofibrosis secondary to polycythaemia vera (32.3% of ruxolitinib group; 30.5% of placebo group) or essential thrombocytopenia (22.6% of ruxolitinib group; 14.3% of placebo group). Patients who enrolled on the trial had resistant or refractory myelofibrosis, or available therapy was contraindicated or not tolerated. All patients on the trial had intermediate-2 risk or high-risk myelofibrosis, a platelet count of at least 100×109/litre and a palpable spleen length of at least 5 cm. The duration of the study was 24 weeks, after which patients could enter an openlabel extension phase. In COMFORT-I, patients were eligible to crossover to ruxolitinib treatment. Before week 24, patients on placebo needed to have symptom worsening and 25% or more spleen volume increase from baseline. After week 24, patients needed to have 25% or more spleen volume increase from baseline.
3.3
COMFORT-II is a multicentre (Europe, including sites in the UK), phase III, randomised, open-label trial that compared ruxolitinib (15 mg or 20 mg twice
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Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis (TA386) daily, n=146) with best available therapy (n=73) in people with primary myelofibrosis (53% of ruxolitinib group; 53% of the best available therapy group), or myelofibrosis secondary to polycythaemia vera (33% of ruxolitinib group; 27% of best available therapy group) or essential thrombocythaemia (14% of ruxolitinib group; 19% of best available therapy group). Best available therapy comprised a range of treatments. The most frequently used were hydroxycarbamide, prednisolone and epoetin alfa. Other treatments used as best available therapy included lenalidomide and thalidomide. All patients on the trial had intermediate-2 or high-risk myelofibrosis, a platelet count of at least 100×109/litre and a palpable spleen length of at least 5 cm. The company stated that the trial population may have been healthier than the general population with myelofibrosis because the trial excluded people with uncontrolled hypertension, unstable angina and a life expectancy of less than 6 months. The duration of the trial was 48 weeks, after which patients could enter an open-label extension phase. In COMFORT-II, patients were eligible to crossover to ruxolitinib treatment. Patients on best available therapy whose disease progressed (defined according to the study protocol as either 25% or more increase in spleen volume from on-study nadir, including baseline, or needing splenectomy, splenic irradiation or leukaemic transformation) could crossover to have ruxolitinib at any time. 3.4
The primary outcome for both COMFORT-I and COMFORT-II was the proportion of patients achieving a spleen volume reduction of 35% or more from baseline, assessed by MRI or CT scan. The primary efficacy outcome was measured at 24 weeks in COMFORT-I and at 48 weeks in COMFORT-II.
3.5
Secondary outcomes for the COMFORT-I trial included maintenance of reduction in spleen volume, reduction in palpable spleen length, change in total symptom score (measured using the modified myelofibrosis symptom assessment form [MF-SAF] v2.0 diary), overall survival, and health-related quality-of-life measures. Secondary outcomes for the COMFORT-II trial included outcomes from the COMFORT-I trial, as well as the time to achieve a spleen volume reduction of 35% or more, progression-free survival, leukaemiafree survival and transfusion dependency. In COMFORT-II, additional overall survival analyses were carried out at 3.5 years follow-up.
3.6
The intention-to-treat (ITT) population was used for all efficacy end points. Patients who stopped treatment or crossed over before 24 weeks (in
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Ruxolitinib for treating disease-related splenomegaly or symptoms in adults with myelofibrosis (TA386) COMFORT-I), or did not have a 48-week assessment of spleen volume (in COMFORT-II because of discontinuation and entering the open-label extension phase) were counted as patients whose disease did not respond (for change in spleen volume and symptom score). 3.7
In COMFORT-I, a statistically significantly greater proportion of patients in the ruxolitinib group achieved a reduction in spleen volume of 35% or more from baseline, compared with the placebo group at 24 weeks (41.9% versus 0.7%; p
